Major depressive disorder (MDD) is a devastating illness with broad socioeconomic effects. Although treatments for MDD have been available for nearly 50 years, available drugs are not always effective and require weeks or even months of treatment. The requirement for long-term antidepressant treatment (ADT) to achieve a therapeutic response has lead to the hypothesis that cellular and molecular adaptations are required. Our studies have characterized key adaptations in signal transduction and gene expression, most notably the cAMP-CREB and BDNF-ERK cascades, and we have begun to determine the functional responses at the behavioral and cellular levels to altered CREB and BDNF, The previous funding period has been productive and the results have contributed to a neurotrophic hypothesis of MDD and ADT that has stimulated a large body of clinical and preclinical studies. The research focus for the next funding period is a combination of extending these findings, as well as initiating new research areas, all of which are consistent with the NIMH Strategic Plan, In the first aim we will use conditional PDE4A mutant mice that we have generated, the first for any PDE4 subtype, to determine if PDE4A is a viable target for novel antidepressant medications that activate the cAMP-CREB cascade. We will utilize a battery of behavioral models, including anxiety, despair, anhedonia, and motivation/reward to assess the phenotype of these animals, and custom microarrays to identify additional downstream gene targets. In the second aim we will use a similar strategy to determine if MKP-1, a dual specificity phosphatase that we have found is increased in MDD patients, is a viable target for development of drugs that activate the BDNF-ERK cascade. Preliminary studies demonstrate that MKP-1 mutant mice are resistant to chronic stress, suggesting that increased MKP-1 expression would increase susceptibility to MDD. The third aim will characterize additional neurotrophic factor regulated gene targets in cellular and behavioral models of MDD. We will also characterize common promoter elements that control cassettes of genes involved in MDD and ADT response, including neuroplasticity, neuroprotection, and synaptic function/formation.